icon_folder.gif   Conference Reports for NATAP  
Interscience Conference on Antimicrobal Agents and Chemotherapy
December 16-19, 2005 Washington DC
Back grey_arrow_rt.gif
New CCR5 Inhibitor Zinc Finger Proteins
  Sangamo BioSciences Announces Breakthrough Results at ICAAC Demonstrating Protection of Cells From HIV Infection Following Treatment with Zinc Finger Nucleases
CCR5 ZFP Therapeutic Expected to Enter Human Clinical Trials in 2006

RICHMOND, Calif., Dec. 17 /PRNewswire-FirstCall/ -- Sangamo BioSciences, Inc. (Nasdaq: SGMO) today announced that data from its program to develop a ZFP Therapeutic(TM) for HIV/AIDS were presented at the 45th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Washington, DC. The study represents the first demonstration that cells can be made resistant to HIV infection by treatment with Sangamo's proprietary zinc finger DNA-binding protein nucleases (ZFN(TM)) designed to specifically disrupt the CCR5 gene.
In its anti-HIV preclinical research program, Sangamo has designed ZFNs that can be used to disrupt the CCR5 gene, a receptor required for HIV entry into immune cells. The researchers found that ZFN-modified cells were resistant to HIV infection whereas control cells were infected when challenged with the virus. Furthermore, when CCR5 expression was experimentally restored in the ZFN-modified cells, HIV was once again able to infect these cells. Sangamo has shown disruption of the CCR5 gene in a number of different cell types including T-cells, the target cell for this therapeutic approach.
"CCR5 is an important target in the fight against HIV/AIDS," stated Edward Lanphier, Sangamo's president and CEO. "Individuals with a natural mutation of their CCR5 gene have been shown to be resistant to HIV infection. Several major pharmaceutical companies have initiated programs to develop small molecule drugs to block HIV binding to CCR5, but in recent months two trials have been halted, one due to reports of liver toxicity of the candidate drug. We believe that using ZFNs to permanently modify the CCR5 gene specifically in T-cells and thus directly block the expression of the protein on the surface of these cells may have several advantages over the systemic effects of other drugs in development."
Small molecule or antibody approaches require the constant presence of antagonist in high enough concentrations to block therapeutically relevant numbers of the CCR5 protein, of which there are approximately 10,000 copies on the surface of each T-cell. In contrast, brief exposure of T-cells to Sangamo's ZFNs has been shown to result in permanent modification of the CCR5 gene and consequent alteration of the CCR5 protein.
"We believe that the data presented at ICAAC provide another important validation of our novel approach to HIV," said Dale Ando, M.D., Sangamo's vice president of therapeutic development and chief medical officer. "By administering ZFNs to patients, we could potentially provide HIV-infected individuals with a reservoir of healthy and uninfectable T-cells that would be available to fight both opportunistic infections and HIV itself. In this program, we have been working in close collaboration with Dr. Carl June at the University of Pennsylvania with the goal of initiating a Phase 1 clinical trial to test our ZFP Therapeutic in 2006."
Dr. Carl June, Director of Translational Research at the Abramson Family Cancer Research Institute at the University of Pennsylvania School of Medicine, is a leader in the field of research testing T-cell therapies for cancer and HIV infection. Dr. June stated, "After the recent negative news regarding trials with pharmacologic blockade of CCR5, it is very important that we focus on positive results involving this well-validated disease target. I am encouraged by Sangamo's findings and look forward to collaborating with the Company further to bring this promising approach into the clinic."
About HIV/AIDS and CCR5
HIV stands for Human Immunodeficiency Virus. HIV infection kills or impairs cells of the immune system, progressively destroying the body's ability to fight infections and certain cancers resulting in AIDS (Acquired Immune Deficiency Syndrome). Individuals diagnosed with AIDS are susceptible to life-threatening diseases called opportunistic infections, which are caused by microbes that usually do not cause illness in healthy people. According to Worldaidsday.org, in 2005, over 3 million people were infected with HIV, which means there are now over 40 million people living with HIV and AIDS.
CCR5 is the chemokine receptor that HIV uses as a coreceptor to gain entry into immune cells. CCR5 is perhaps the most important of the known coreceptors for HIV, since the most commonly transmitted strains of HIV are strains that bind to CCR5 -- so-called "R5" strains. A small fraction of the population carries a mutation in their CCR5 gene, called the delta32 mutation. This mutated version of the gene produces malformed CCR5 proteins, which cannot be used by HIV as a coreceptor. Individuals that have mutant delta 32 versions of both of their CCR5 genes are resistant to infection by R5 HIV strains.
About Sangamo
Sangamo BioSciences, Inc. is focused on the research and development of novel DNA-binding proteins for therapeutic gene regulation and modification. The most advanced ZFP Therapeutic(TM) development programs are currently in Phase I clinical trials for evaluation of safety in patients with diabetic neuropathy and peripheral artery disease. Other therapeutic development programs are focused on macular degeneration, ischemic heart disease, congestive heart failure, neuropathic pain, and infectious and monogenic diseases. Sangamo's core competencies enable the engineering of a class of DNA-binding proteins known as zinc finger DNA-binding proteins (ZFPs). By engineering ZFPs that recognize a specific DNA sequence Sangamo has created ZFP transcription factors (ZFP TF(TM)) that can control gene expression and, consequently, cell function. Sangamo is also developing sequence-specific ZFP Nucleases (ZFN(TM)) for therapeutic gene modification as a treatment for a variety of monogenic diseases, such as sickle cell anemia, and for infectious diseases, such as HIV. Sangamo has established several Enabling Technology Agreements with companies to apply its ZFP Technology to enhance the production of protein pharmaceuticals. For more information about Sangamo, visit the company's web site at www.sangamo.com.
This press release may contain forward-looking statements based on Sangamo's current expectations. These forward-looking statements include, without limitation, references to the effectiveness of using ZFNs to treat patients with HIV, the initiation of clinical trials, research and development of novel ZFP TFs and ZFNs and therapeutic applications of Sangamo's ZFP technology platform. Actual results may differ materially from these forward- looking statements due to a number of factors, including uncertainties relating to the further study and development of our ZFN technology, initiation of clinical trials of ZFP Therapeutics, whether such clinical trials will validate and support tolerability and efficacy of ZFP Therapeutics, the effectiveness of our research and development of novel ZFP TFs and ZFNs and therapeutic applications of Sangamo's ZFP technology platform, technological challenges, Sangamo's ability to develop commercially viable products and technological developments by our competitors. See the company's SEC filings, and in particular, the risk factors described in the company's Annual Report on Form 10-K and its most recent 10-Q. Sangamo BioSciences, Inc. assumes no obligation to update the forward-looking information contained in this press release.
Commercialization of ZFP Therapeutics.
We plan to develop and commercialize ZFP-Therapeutics in partnership with pharmaceutical and biotechnology companies. For certain ZFP-Therapeutics we intend to negotiate partnerships with terms that will provide partners with exclusive rights to the regulation of specific genes for certain clinical indications and geographic areas covered under the agreement. For other ZFP-Therapeutics, we intend to retain certain commercial product rights or negotiate partnerships for such products after substantial internal development.
Towards Gene Knock Out Therapy for AIDS/HIV: Targeted Disruption of CCR5 Using Engineered Zinc Finger Protein Nucleases (ZFNs)
Y. JOUVENOT1, E. PEREZ 2, F. D. URNOV 1, C. BEAUSEJOUR 1, J. ROCK 1, Y. L. LEE 1, J. C. MILLER 1, E. J. REBAR 1, M. C. HOLMES 1, D. ANDO 1, J. RILEY 2, P. D. GREGORY 1, C. JUNE 2; 1Sangamo Biosciences Inc, Richmond, CA, 2Univ. of Pennsylvania, Philadelphia, PA.
Background: HIV requires the CD4 co-receptors CCR5 or CXCR4 to infect its target cells. Loss of HIV co-receptors is therefore an attractive therapy for HIV patients, yet no current methods permit efficient therapeutic disruption of a chosen gene in the human genome. We have developed designed zinc-finger protein nucleases (ZFNs) to target the CCR5 gene and create a double strand break (DSB) at predetermined sequences. Natural DNA repair pathways, including Non-Homologous End Joining, subsequently repair the DSB. This repair is error prone and thus results in permanent disruption of the target gene.
Methods: Designed ZFPs that recognize coding sequences within the CCR5 gene were fused to the FokI catalytic domain to create ZFNs in which the DNA binding specificity of the ZFP determines DSB location. ZFN binding and cleavage was determined in vitro using ELISA-based DNA binding assays and PAGE. Vectors encoding the ZFNs were introduced into human cells for in vivo assessment of function. Disruption was measured by determining the sequence at the targeted site.
Results: Cell-based assays revealed that CCR5-ZFNs generated DSBs in vivo leading to high efficiency target gene disruption in transiently transfected cells even in the absence of selective pressure. These results have been confirmed in relevant primary cell types (monocytes, CD4+ T cells). HIV challenge assays using cells pre-treated with the CCR5-ZFNs are in progress, although it is well established that a patient's cells carrying a deletion within the CCR5 gene are resistant to infection despite repeated exposure to the R5-tropic virus.
Conclusion: These data support the investigation of ZFNs as a possible method for the therapeutic modification of isolated patient cells to generate HIV resistant cell populations.
SOURCE Sangamo BioSciences, Inc.
CONTACT: Elizabeth Wolffe, Ph.D. of Sangamo BioSciences, Inc.,
+1-510-970-6000, ext. 271, or ewolffe@sangamo.com